Significance Leptin is a recently discovered hormone which was identified by positional cloning of a gene, which when defective in a rodent model (the ob/ob mouse), results in hyperphagia, obesity, and insulin resistance. Administration of recombinant leptin to mice reduces food intake and causes weight loss. In addition, leptin administration has been reported to increase energy expenditure in mice. It has been hypothesized that leptin acts as a peripheral signal of adipose tissue stores to the central nervous system to regulate body weight and limit adiposity. If this is the case, leptin has therapeutic potential for the treatment of obesity. The CRPRC has a number of rhesus monkeys which have developed spontaneous adult-onset obesity. Objectives To examine the effects of exogenous leptin administration (1.0, 3.3, and 10.0 mg/kg/day on food intake, neuroendocrine function, and energy expenditure in obese and lean rhesus monkeys. Other obese and lean monkeys are receives injections of vehicle only as controls for the leptin-injected animals. Results Daily food intake was recorded and body weight determined twice weekly. Changes of body fat content were assessed by dual energy x-ray absorbtiometry (DEXA). To assess the effects of leptin administration on thermogenesis in rhesus monkeys RMR was determined by indirect calorimetry in cages in sealed chambers equipped with flowmeters and instruments for measuring oxygen and carbon dioxide (indirect calorimetry). To assess the effects of leptin administration on hypothalamic-pituitary-adrenal axis function, ACTH stimulation tests were conducted. Insulin sensitivity was assessed before after leptin or placebo administration by use of IV glucose tolerance tests. The experiments have been completed and the data are currently being analyzed. Future Directions We will continue to use the rhesus monkey model to investigate the regulation of leptin secretion and leptin action. KEYWORDS leptin, obesity, diabetes, food intake, resting metabolic rate, insulin sensitivity